Injury to the duodenal mucosa, though decreasing in incidence, has increased in virulence over the past several decades. Despite the advent of potent antisecretory medications and the discovery of the role of Helicobacter pylori in the pathogenesis of mucosal injury, mucosal ulceration with resultant complications such as perforation and bleeding remains a problem for subjects in intensive care and those taking non-steroidal anti-inflammatory drugs. Furthermore, functional nausea and dyspepsia, a disease for which available therapies are limited, afflicts millions of subjects. We have provided data to support the novel hypothesis that the entire duodenal acid load is absorbed as CO2, with multiple interconversions between H+ and CO2 facilitated by soluble and membrane-bound isoforms of carbonic anhydrase (CA). In this fashion, large quantities of H+ can be readily absorbed without the risk of overly acidifying the epithelial cells or the submucosal interstitium. According to this hypothesis, the primary function of the large amount of epithelial HCO3- secretion is to convert luminal H+ into the more benign and readily absorbable H+ equivalent CO2. The duodenum also has a well- developed chemosensory system that promptly responds to luminal acid with a coordinated set of protective responses, such as an increase in mucosal blood flow and mucus secretion. We intend to further test this hypothesis by examining in detail how CO2 is absorbed across the apical membrane of the epithelial cells, how membrane- bound phosphatases participate in the regulation of HCO3- secretion, and how submucosal acid sensors transduce the luminal acid signal into efferent physiological responses, as well as the perception of sensations such as nausea. Since duodenal protective mechanisms are directly related to the mechanism of duodenal acid absorption, investigations of this nature will provide new information regarding duodenal host defenses from acid injury. This knowledge can then be used to help design new therapies designed at strengthening the ability of the duodenum to resist acid injury. Furthermore, the knowledge regarding the mechanism of duodenal acid sensing can be used to design therapies to effectively treat functional nausea and dyspepsia.